At sea level, exercise limitation in normal man is imposed by those factors which control or determine the maximal cardiac output and its distribution. With the possible exception of Olympic class athletes, pump function of the thorax and alveolar gas exchange do not impose an important limitation on exercise at sea level in normal man. However, in normal man at high altitude or in patients with functional lung impairment at sea level, the lungs and thorax can impose an important additional limitation on exercise capacity. Limitations potentially arise from: 1) increased mechanical load on respiratory muscles; 2) Impaired alveolar gas exchange by a low O2 diffusing capacity or low O2 driving pressure (high altitude) or inefficient regional matching of ventilation and blood flow; 3) Restrictions imposed on cardiovascular function by increased right ventricular afterload, exaggerated mechanical heart-lung interactions, e.g., increased stiffness of the lungs and cardiac fossa, causing impairment of diastolic filling or cardiodepressor reflexes from the lung. The relative importance of these potential sources of exercise limitation in lung disease are unclear and difficult to approach experimentally in man. There have been numerous animal models developed for examining mechanisms of exercise limitation caused by impaired cardiovascular function, but virtually none for examining mechanisms of limitation imposed by impaired lung function. By pneumonectomy in dogs, we can increase in a reproducible way the stiffness and reduce the diffusing capacity of the lungs and increase pulmonary vascular resistance. This will in turn increase work of breathing, reduce the reserve for alveolar gas exchange, increase right ventricular afterload, and may also reduce preload to the heart. Over the past 31/2 years we have developed the techniques to examine each of these potential sources of limitation to exercise in awake dogs using minimally invasive methods and limited use of chronic instrumentation. Our plan is to employ these methods to characterize the nature and importance of the potential sources of limitations in exercise capacity by loss of lung parenchyma.